Reversal of glucocorticoid-induced skin atrophy

ABSTRACT

The present invention is directed to the topical administration of a retinoid-containing pharmaceutical composition for reversing the effects of glucocorticoid-induced skin atrophy.

This is a continuation-in-part of application Ser. No. 925,935, filedNov. 3, 1986 now U.S. Pat. No. 4,889,847.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a method for reversing the effects ofglucocorticoid-induced skin atrophy by the topical administration ofretinoids.

2. Description of the Prior Art

The most widely prescribed drugs to treat dermatologic disease areglucocorticosteroids. Approximately 50% of prescriptions written bydermatologists are for topical glucocorticosteroids. Since theintroduction of these substances in the early 1950's for dermatologicdisease, topical corticosteroid therapy continues to be the mainstay forthe management of a broad spectrum of inflammatory dermatoses. Althoughsystemic corticosteroids are often required in some dermatologicdiseases, topical treatment is preferred in most responsive casesbecause it causes fewer systemic adverse effects.

Topical corticosteroids are generally most effective in the treatment ofacute and chronic dermatoses such as seborrheic or atopic dermatitis,contact dermatitis of the irritant or allergic type, localizedneurodermatitis, anogenital pruritus and psoriasis.

Individual topical corticosteroid preparations vary in anti-inflammatorypotency and clinical efficacy. Therapeutic efficacy of a particularsteroid can often be enhanced by increasing the concentration or byusing occulsive dressings. Topical corticosteroids may be groupedaccording to relative anti-inflammatory potency. Still activity may varyconsiderably depending upon the vehicle, the site of application,disease, the individual patient, and whether or not an occlusivedressing is used.

Although some dermatoses may require therapy with a potentcorticosteroid initially, treatment with hydrocortisone, betamethasone,dexamethasone, methylprednisolone, or prednisolone, is often sufficientand is less likely to cause adverse reactions. Although fluorinatedcorticosteroids are generally potent and efficacious, fluorination isnot essential for increased anti-inflammatory potency (e.g.,hydrocortisone valerate has greater anti-inflammatory activity than doesbetamethasone or dexamethasone). Potent corticosteroids are customarilyused for severe or resistant dermatoses such as psoriasis and chronicneurodermatitis. Dermatoses such as discoid lupus erythematosus, lichenplanus, granuloma annulare, and psoriasis of palms, soles, elbows andknees or psoriatic plaques usually require potent corticosteroids.

In general, topical application of corticosteroids does not producesystemic side reactions, although abnormal laboratory tests may occur,viz., decreased adrenal production of cortisol. However, systemiccorticosteroid side effects may occur when the drugs are used on largeareas of the body, for prolonged periods of time, with an occlusivedressing, and/or in infants and children. These include Cushing'sdisease, acne, osteoporosis, etc.

Potent topical corticosteroids often cause dermatologic side effects.These are most likely to occur in intertriginous and facial areas andare most severe with fluorinated corticosteroids, especially on the facewhere steroids are rapidly absorbed. Local corticosteroid side effectsoccur most frequently with occlusive dressings, especially withprolonged therapy.

Local side effects have become more frequent with the clinical use ofnewer and more potent glucocorticosteroidal analogs. The most commonadverse reaction is skin atrophy, i.e., a thinning of the epidermis anddermis accompanied by telangiectasia and striae. Minimal trauma toatrophic skin may also produce purpuric lesions. Other dermatologic sideeffects include acneiform eruption, pruritus, hypertrichosis,rosacea-like eruptions on the face, perioral dermatitis, burning orstinging sensation, folliculitis, and hypopigmentation. Skin ulcerationhas occurred in patients with impaired circulation. Because of the highprevalence and seriousness of skin atrophy, it would be very valuable tohave available a preparation which was anti-inflammatory but did notcause skin thinning or striae; the latter is a permanent scar or onewhich would reverse the effects of skin atrophy after they appear.

Topical retinoids such as tretinoin (all-trans-retinoic acid) have beenused by dermatologists for almost twenty years. For example, tretinoinis used topically in the treatment of acne vulgaris, primarily gradesI-III, in which comedones, papules, and pustules predominate.

In concentrations of 0.1% to 0.3%, tretinoin has been used successfullyin the reatment of other skin conditions such as psoriasis, ichthyosiscongenita, Darier's disease, epidermolytic hyperkeratosis, senilecomedones, senile keratosis, trichostasis, flat warts and basal cellcarcinomas.

SUMMARY OF THE INVENTION

The present invention is directed to a method for reversing the effectsof glucocorticoid-induced skin atrophy. The method comprises the topicaladministration of retinoids. The retinoids may be any natural and/orsynthetic analog which possess the biological activity of vitamin A.

In co-pending application Ser. No. 925,935 a method for preventingglucocorticoid-induced skin atrophy by the topical administration ofretinoids such as tretinoin is described. We have now found that inaddition to preventing glucocorticoid-induced skin atrophy, topicaladministration of retinoids will reverse the effects ofglucocorticoid-induced skin atrophy.

DETAILED DESCRIPTION OF THE INVENTION

The invention relates to the use of retinoids for reversing the effectsof glucocorticoid-induced skin atrophy, a side effect of prolongedtopical glucocorticoid therapy for dermatological diseases.

Retinoids have been defined narrowly as comprising simply vitamin A(retinol) and its derivatives, such as vitamin A aldehyde (retinal) andvitamin A acid (retinoic acid), which comprise so-called naturalretinoids. However, subsequent research has resulted in a much largerclass of chemical compounds that are deemed retinoids due to theirbiological similarity to vitamin A and its derivatives. Compounds usefulin the present invention include all natural and/or synthetic analogs ofvitamin A or retinol-like compounds which possess the biologicalactivity of vitamin A in the skin. These include: regulation ofepithelial cell differentiation in the epidermis, for example,keratinocytes; stimulation of new collagen synthesis in the dermis, andproduction of new blood vessels (angiogenesis). Accordingly, as usedherein for purposes of the present invention, the term "retinoid" willbe understood to include any of the foregoing compounds. Examples ofsuitable retinoids in the present invention are set forth in Table I,although it will be understood that the invention is not limitedthereto.

                  TABLE I                                                         ______________________________________                                        all-trans-retinoic acid                                                       13-cis-retinoic acid                                                          (all-E)-9-(4-methoxy-2,3,6-                                                   trimethylphenyl)-3,7-dimethyl-2,4,6,8-                                        nonatetraenoic acid ethyl ester                                               (all-E)-9-(4-methoxy-2,3,6-                                                   trimethylphenyl)-3,7-dimethyl-2,4,6,8-                                        nonatetraenoic acid                                                           N-ethyl-9-(4-methoxy-2,3,6-trimethyl-                                         phenyl)-3,7,-dimethyl-2,4,6,8-                                                nonatetraenamide                                                              (E,E)-9-(2,6-dichloro-4-methoxy-3-                                            methylphenyl)-3,7-dimethyl-2,4,6,8-                                           nonatetraenoic acid ethyl ester                                               7,8-didehydroretinoic acid                                                    (E,E)-4-[2-methhy-4-(2,6,6-trimethyl-                                         1-cyclohexen-1-yl)-1,3-butadienyl]benzoic acid                                (E)-4-[4-methyl-6-(2,6,6-trimethyl-                                           1-cyclohexen-1-yl)-1,3,5-hexa-                                                treinyl]benzoic acid                                                          (all-E)-3,7-dimethyl-(3-thienyl)-                                             2,4,6,8-nonatetraenoic acid                                                   (E,E,E)-3-methyl-7-(5,6,7,8-tetrahydro-                                       5,5,8,8.-tetramethyl-2-naphthalenyl)-                                         2,4,6-octatrienoic acid                                                       (E)-6-[2-(2,6,6-trimethyl-1-cyclohexen-                                       1-yl)ethenyl]-2-naphthalenecarboxylic acid                                    (E,E,E)-7-(2,3-dihydro-1,1,3,3-tetra-                                         methyl-1H-inden-5-yl)-3-methyl-                                               2,4,6-octatrienoic acid                                                       (E)-4-[2-(2,3,-dihydro-1,1,3,3-tetramethyl-                                   1H-inden-5-yl)-1-propenyl]benzoic acid                                        (E)-4-[2-(5,6,7,8-tetrahydro-5,5,8,8-                                         tetramethyl-2-naphthalenyl-1-                                                 propenyl]benzoic acid                                                         (E)-4-[2-(5,6,7,8-tetrahydro-3-methyl-                                        5,5,8,8,-tetramethyl-2-naphthalenyl-1-                                        propenyl]benzoic acid                                                         (E)-1,2,3,4-tetrahydro-1,1,4,4-tetramethyl-                                   6-(1-methyl-2-phenylethenyl)naphthalene                                       6-(1,2,3,4-tetrahydro-1,1,4,4-tetramethyl-                                    6-naphthyl-2-naphthalenecarboxylic acid                                       (E)-6-[2-(4-(ethylsulfonyl)phenyl]-1-                                         methylethenyl]-1,2,3,4-tetrahydro-                                            1,1,4,4-tetramethylnaphthalene                                                4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-                                   2-naphthalenyl)ethynyl]benzoic acid                                           (E)-2-(1,1,4,4-tetramethyl-1,2,3,4-tetra-                                     hydronaphth-7-yl)-1-[4-tetrazol-                                              5-yl)phenyl]-1-propene                                                        (E)-4-[2-(5,6,7,8-tetrahydro-7-hydroxy-                                       5,5,8,8-tetramethyl-2-naphthalenyl)-                                          1-propenyl]benzyl alcohol                                                     retinoyl palmitate, retinyl palmitate                                         retinyl propionate                                                            (6-(3-(1-adamantyl)-4-methoxyphenyl)-                                         2-naphthoic acid)                                                             ______________________________________                                    

Also encompassed within the term "retinoid" are geometric andstereoisomers of the retinoids.

A pharmaceutical composition containing a retinoid as the activeingredient in intimate admixture with a pharmaceutical carrier can beprepared according to conventional pharmaceutical compoundingtechniques, such as those known for topical application ofall-trans-retinoic acid. The carrier may take a wide variety of physicalforms such as creams, dressings, gels, lotions, ointments or liquids.The retinoid will be present in an amount from about 0.00001% by weightto about 3.0% by weight, depending on the potency of the retinoid. Asuitable topical retinoid preparation in a gel vehicle is Retin-A™,which contains 0.01% to 0.1% by weight of active ingredient, produced byOrtho Pharmaceutical Corporation. The retinoid may be employed incombination with a glucocorticoid in the same vehicle.

The retinoid may be applied topically before application of theglucocorticoid, simultaneously with the application of theglucocorticoid, or after the application of the glucocorticoid.

The following example describes the invention in greater particularity,and is intended to be a way of illustrating but not limiting theinvention.

EXAMPLE

Skin atrophy was produced in SKH-hairless-1 albino mice by the topicalapplication of various glucocorticoids one time daily, five days perweek for three weeks to their dorsal flanks. The glucocorticoidsincluded: clobetasol propionate (0.05%); triamcinolone acetonide (0.5%)or fluocinolone acetonide (0.05%) dissolved in an alcohol: propyleneglycol vehicle (70:30, v/v). The atrophied mice were divided intovarious treatment groups and either vehicle or all-trans-retinoic acid(0.1%) in vehicle was topically applied one time daily, five days perweek for two weeks to the dorsal flank skin previously treated withglucocorticoids. Skin-fold thickness measurements of the treated siteswere taken with an electronic digital caliper prior to initial treatmentand approximately 72 hours following one week and two weeks oftreatments. The results are given in Table II.

                                      TABLE II                                    __________________________________________________________________________    REPAIR/REVERSAL OF GLUCOCORTICOID-INDUCED SKIN ATROPHY                        BY ALL-TRANS-RETINOIC ACID (RA)                                                                            REPAIR/REVERSAL OF SKIN ATROPHY                  SKIN ATROPHY       PERCENT                   % REPAIR/REVERSAL                TREATMENT  DOSE (%)                                                                            N SKIN ATROPHY                                                                            TREATMENT                                                                             DOSE (%)                                                                            N WEEK 1 WEEK                      __________________________________________________________________________                                                        2                         CLOBETASOL 0.05  6 34.8      VEHICLE --    3 9.5    20.0                      PROPIONATE                   RA      0.1   3 36.4   45.5                      TRIAMCINOLONE                                                                            0.5   6 39.2      VEHICLE --    3 15.2   28.3                      ACETONIDE                    RA      0.1   3 40.2   53.3                      FLUOCINOLONE                                                                             0.05  6 38.6      VEHICLE --    3 29.5   34.7                      ACETONIDE                    RA      0.1   3 30.6   50.0                      __________________________________________________________________________     ALL THREE GLUCOCORTICOIDS INDUCED SKIN ATROPHY TO SIMILAR DEGREE IN THE       HAIRLESS MOUSE, (E.G., 34.8% BY CLOBETASOL PROPIONATE, 39.2% BY               TRIAMCINOLONE ACETONIDE AND 38.6% BY FLUOCINOLONE ACETONIDE). TOPICAL         ALLTRANS-RETINOIC ACID PRODUCED INCREASES IN SKINFOLD THICKNESS OVER          VEHICLE CONTROL AND CLEARLY ENHANCED THE REPAIR/REVERSAL OF                   GLUCOCORTICOIDINDUCED SKIN ATROPHY.                                           N = NO. OF MICE                                                          

The results shown in Table II clearly demonstrate that theadministration of all-trans-retinoic acid reverses the effects of skinatrophy induced by topical glucocorticoid therapy.

What is claimed is:
 1. A method for reversing the effects ofglucocorticoid-induced skin atrophy which comprises topicallyadministering to the glucocorticoid-treated skin a pharmaceuticalcomposition comprising an effective amount of a retinoid and apharmaceutically acceptable carrier.
 2. The method of claim 1 whereinsaid retinoid comprises from about 0.00001% by weight to about 3.0% byweight of said composition.
 3. The method of claim 1 wherein saidcomposition further comprises a glucocorticoid.
 4. The method of claim 3wherein the glucocorticoid is dexamethasone.
 5. The method of claim 1wherein said retinoid is selected from the group consisting ofall-trans-retinoic acid, 13-cis-retinoic acid,(all-E)-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoicacid ethyl ester,(all-E)-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoicacid,N-ethyl-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenamide,(E,E)-9-(2,6-dichloro-4-methoxy-3-methylphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoicacid ethyl ester, 7,8-didehydroretinoic acid,(E,E)-4-[2-methyl-4-(2,6,6-trimethyl-1-cyclohexen-1-yl)-1,3-butadienyl]benzoicacid,(E)-4-[4-methyl-6-(2,6,6-trimethyl-1-cyclohexen-1-yl)-1,3,5-hexatrienyl]benzoicacid, (all-E)-3,7-dimethyl-3-thienyl)-2,4,6,8-nonatetraenoic acid,(E,E,E)-3-methyl-7-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-2,4,6-octatrienoicacid,(E)-6-[2-(2,6,6-trimethyl-1-cyclohexen-1-yl)ethenyl]-2-naphthalenecarboxylicacid,(E,E,E)-7-(2,3,-dihydro-1,1,3,3-tetramethyl-1H-inden-5-yl)-3-methyl-2,4,6-octatrienoicacid,(E)-4-[2-(2,3-dihydro-1,1,3,3-tetramethyl-1H-inden-5-yl)-1-propenyl]-benzoicacid,(E)-4-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl-1-propenyl]benzoicacid,(E)-4-[2-(5,6,7,8-tetrahydro-3-methyl-5,5,8,8-tetramethyl-2-naphthalenyl-1-propenyl]benzoicacid,(E)-1,2,3,4-tetrahydro-1,1,4,4-tetramethyl-6-(1-methyl-2-phenylethenyl)-naphthalene,6-(1,2,3,4-tetrahydro-1,1,3,4-tetramethyl-6-naphthyl)-2-naphthalenecarboxylicacid,(E)-6-[2-(4-(ethylsulfonyl)phenyl]-1-methylethenyl]-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene,4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)ethynyl]benzoicacid,(E)-2-(1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphth-7-yl-1-[4-tetrazol-5-yl)phenyl]-1-propene,(E)-4-[2-(5-6,7,8-tetrahydro-7-hydroxy-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl]benzylalcohol, retinoyl palmitate, retinyl palmitate, retinyl propionate and(6-(3-(1-adamantyl)-4-methoxyphenyl)-2-naphthoic acid).
 6. The method ofclaim 1 wherein said retinoid is all-trans-retinoic acid.
 7. The methodof claim 1 wherein said retinoid is 13-cis-retinoic acid.
 8. The methodof claim 1 wherein said retinoid is selected from the group consistingof(E)-4-[4-methyl-6-(2,6,6-trimethyl-1-cyclohexen-1-yl)-1,3,5-hexatrienyl]benzoicacid,4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)ethynyl]benzoicacid, and(E)-4-[2-(5,6,7,8-tetrahydro-7-hydroxy-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl]-benzylalcohol.
 9. The method of claim 3 wherein said retinoid is selected fromthe group consisting of all-trans-retinoic acid, 13-cis-retinoic acid,(all-E)-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoicacid ethyl ester,(all-E)-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoicacid,N-ethyl-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenamide,(E,E)-9-(2,6-dichloro-4-methoxy-3-methyl-phenyl-3,7-dimethyl-2,4,6,8-nonatetraenoicacid ethyl ester, 7,8-didehydroretinoic acid,(E,E)-4-[2-methyl-4-2,6,6-trimethyl-1-cyclohexen-1-yl)-1,3-butadienyl]benzoicacid,(E)-4-[4-methyl-6-(2,6,6-trimethyl-1-cyclohexen-1-yl)-1,3,5-hexatrienyl]benzoicacid, (all-E)-3,7-dimethyl-(3-thienyl)-2,4,6,8-nonatetraenoic acid,(E,E,E)-3-methyl-7-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-2,4,6-octatrienoicacid,(E)-6-[2-(2,6,6-trimethyl-1-cyclohexen-1-yl)ethenyl]-2-naphthalenecarboxylicacid,(E,E,E)-7-(2,3-dihydro-1,1,3,3-tetramethyl-1H-inden-5-yl)-3-methyl-2,4,6-octatrienoicacid,(E)-4-[2-(2,3-dihydro-1,1,3,3-tetramethyl-1H-inden-5-yl)-1-propenyl]benzoicacid,(E)-4-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl-1-propenyl]benzoicacid,(E)-4-[2-(5,6,7,8-tetrahydro-3-methyl-5,5,8,8-tetramethyl-2-naphthalenyl-1-propenyl]benzoicacid,(E)-1,2,3,4-tetrahydro-1,1,4,4-tetramethyl-6-(1-methyl-2-phenylethenyl)-naphthalene,6-(1,2,3,4-tetrahydro-1,1,4,4-tetramethyl-6-naphthyl)2-naphthalenecarboxylicacid,(E)-6-[2-(4(ethylsulfonyl)phenyl]-1-methylethenyl]-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene,4[-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2naphthalenyl)ethynyl]benzoicacid,(E)-2-(1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphth-7-yl)-1-[4-tetrazol-5-yl)phenyl]-1-propene,(E)-4-[2-(5,6,7,8-tetrahydro-7-hydroxy-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl]benzylalcohol, retinoyl palmitate, retinyl palmitate, retinyl propionate and(6-(3-(1-adamantyl)-4-methoxyphenyl)-2-naphthoic acid).
 10. The methodof claim 3 wherein said retinoid is all-trans-retinoic acid.
 11. Themethod of claim 3 wherein said retinoid is 13-cis-retinoic acid.
 12. Themethod of claim 3 wherein said retinoid is selected from the groupconsisting of(E)-4-[4-methyl-6-(2,6,6-trimethyl-1-cyclohexen-1-yl)-1,3,5-hexatrienyl]benzoicacid,4-[(5,6,7,8-tetrahydro-5-5,8,8-tetramethyl-2-naphthalenyl)-ethynyl]benzoicacid, and(E)-4-[2-(5,6,7,8-tetrahydro-7-hydroxy-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl]-benzylalcohol.
 13. The method of claim 4 wherein said retinoid is selectedfrom the group consisting of all-trans-retinoic acid, 13-cis-retinoicacid,(all-E)-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoicacid ethylester,(all-E)-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoicacid,N-ethyl-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenamide,(E,E,)-9-(2,6-dichloro-4-methoxy-3-methylphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoicacid ethyl ester, 7,8-didehydroretinoic acid,(E,E)-4-[2-methyl-4-(2,6,6-treimethyl-1-cyclohexen-1-yl)-1,3-butadienyl]benzoicacid,(E)-4-[4-methyl-6-(2,6,6-triemthyl-1-cyclohexen-1-yl-1,3,5-hexatrienyl]benzoicacid, (all-E)-3,7-dimethyl-(3-thienyl)-2,4,6,8-nonatetraenoic acid,(E,E,E)-3-methyl-7-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-2,4,6-octatrienoicacid,(E)-6-[2-(2,6,6-trimethyl-1-cyclohexen-1-yl)ethenyl]-2-naphthalenecarboxylicacid,(E,E,E)-7-(2,3-dihydro-1,1,3,3-tetramethyl-1H-inden-5-yl)-3-methyl-2,4,6-octatrienoicacid,(E)-4-[2-(2,3-dihydro-1,1,3,3,-tetramethyl-1H-inden-5-yl)-1-propenyl]benzoicacid,(E)-4-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl-1-propenyl]benzoicacid,(E)-4-[2-(5,6,7,8-tetrahydro-3-methyl-5,5,8,8-tetramethyl-2-naphthalenyl-1-propenyl]benzoicacid,(E)-1,2,3,4-tetrahydro-1,1,4,4-tetramethyl-6-(1-methyl-2-phenylethenyl)naphthalene,6-(1,2,3,4-tetrahydro-1,1,4,4-tetramethyl-6-naphthyl)-2-naphthalenecarboxylicacid,(E)-6-[2-(4-ethylsulfonyl)phenyl]-1-methylethyl]-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene,4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)ethynyl]benzoicacid,(E)-2-(1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphth-7-yl)-1-[4-tetrazol-5-yl)phenyl]-1-propene,(E)-4-[2-(5,6,7,8-tetrahydro-7-hydroxy-5,5,8,8-tetramethyl-2-napthalenyl)-1-propenyl]benzylalcohol, retinoyl palmitate, retinyl palmitate, retinyl propionate and(6-(3-(1-adamantyl)-4-methoxyphenyl)-2-naphthoic acid.
 14. The method ofclaim 4 wherein said retinoid is all-trans-retinoic acid.
 15. The methodof claim 4 wherein said retinoid is 13-cis-retinoic acid.